Collagen– <scp>ORC</scp> Versus Standard Treatment in Diabetic Foot Ulcers: A Systematic Review and Meta‐Analysis of Randomised Trials

Diabetic foot ulcers (DFUs) are a major cause of infection, hospitalisation, and amputation. Collagen-based dressings-especially collagen combined with oxidised regenerated cellulose (ORC)-are proposed to improve healing by modulating matrix metalloproteinases (MMPs), stabilising the extracellular matrix (ECM), and tempering inflammation; some formulations also include antimicrobial or bioactive adjuncts. We conducted a systematic review of randomised controlled trials (RCTs) following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance. Adults with DFUs were eligible. Interventions included collagen-alone or collagen-combination dressings (e.g., collagen-oxidised regenerated cellulose [collagen-ORC]/silver, collagen-chitosan) versus standard of care (SOC) or alternative dressings. To ensure comparable outcomes, the quantitative synthesis was pre-specified and restricted to complete wound closure (yes/no, intention-to-treat [ITT]) from collagen-combination RCTs with aligned constructs; other outcomes were synthesised narratively. Meta-analyses were performed in Microsoft Excel using Mantel-Haenszel methods for risk ratios (RR) with a fixed-effect primary model and DerSimonian-Laird random-effects sensitivity analysis; heterogeneity was summarised with Cochran's Q, between-study variance (τ²), and Higgins' I² statistic (I²), and a 95% prediction interval was reported for random-effects. (Protocol not registered). Six studies (five randomized controlled trials and one single-blinded non-randomized comparative study; total n = 314) met inclusion. In a focused meta-analysis of the two collagen-combination RCTs, treatment was associated with a higher probability of complete wound closure versus control (RR 1.69, 95% confidence interval [CI] 1.05-2.72; I² = 0%). One assessor-blinded RCT of collagen alone reported higher 12-week closure versus a placebo dressing and was not pooled due to heterogeneity. Across studies, signals also favored collagen-based care for earlier area reduction and, in one trial, fewer infection-related withdrawals; mechanistic work showed reductions in MMP-9/TIMP-2. However, most trials were small and single-centre, comparators and adjuncts varied, follow-up was short (~8 days-24 weeks, clinical endpoints typically 4-20 weeks), outcome definitions were non-standardised, and key confounders (off-loading, infection management, vascular status, glycaemic control) were inconsistently addressed. Collagen-based dressings-particularly collagen-combination formulations-appear to improve complete closure when added to the standard of care (SOC) for diabetic foot ulcers (DFUs), but the evidence is limited by study size, heterogeneity, and risk of bias. Larger, prospectively registered, multicentre RCTs with standardised outcomes and longer follow-up are needed to define clinical and cost-effectiveness and to identify which patients benefit most. Collagen-ORC dressings show promise as an adjunctive treatment for DFUs by influencing the inflammatory microenvironment and supporting tissue repair. However, the certainty of the current evidence remains limited, highlighting the need for further high-quality randomised studies.